Background: Bleeding from massive hemorrhage in trauma and post-partum are a major cause of death worldwide. There have been two large randomized controlled trials, in trauma and post-partum hemorrhage that have shown administration of TXA within 3 hrs of bleeding onset reduces death due to bleeding. The current meta-analysis that we are going to best panerai replica review sought to quantify the effect of treatment delay in acute severe bleeding by analyzing individual patient-level data from the two randomized clinical trials mentioned above.

What They Did:

Individual patient-level data meta-analysis of 2 randomized trials done with more than 1000 patients each, that assessed the effects of antifibrinolytics in acute severe bleeding.

Survival Benefit Decreased by 10% for Every 15 min of Treatment Delay Until 3hr, After Which There was no Benefit

Strengths:

Trials that were RCT and had over 1000 patients were selected to reduce selection bias.

Primary outcome was death due to bleeding and not all-cause mortality, as antifibrinolytics would not affect other causes of death

Quality of included trials assessed by evaluating sequence generation, allocation concealment, blinding, data completeness, and risk of selective reporting, all of which are important to minimize bias in studies

All analyses were done according to the intention-to-treat principle

The funders of the CRASH-2 and WOMAN trials had no role in this study design, data collection, data analysis, data interpretation, or writing of this meta-analysis

Assessed the effect of treatment delay on treatment effectiveness

Limitations:

In trauma patients, the exact time of bleeding onset is often unknown, making some measurement error a possibility and potentially underestimating the effectiveness of TXA

In post-partum hemorrhage the time of bleeding onset was the time of birth, making some measurement error a possibility and potentially overestimating the effectiveness of TXA

It is possible that deaths due to bleeding and deaths from vascular occlusive events could have been misclassified (i.e. DIC)

More randomized clinical trials could have been included in this meta-analysis, but smaller trials are underpowered to assess effects on death

Discussion:

The authors of the paper also evaluated the relative treatment benefit observed by 60 minute intervals of treatment delay from time of onset of bleeding. There appears to be no additional benefit when TXA was given in the first hour, but it is also important to mention that a higher proportion of penetrating injuries are seen and treated in this time period, and many of them may have been unsurvivable injuries, therefore making the effect seem non-beneficial during this hour

Author Conclusion: “Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid.”

Clinical Take Home Point: In patients with massive bleeding from trauma or post-partum hemorrhage, giving TXA as soon as bleeding is suspected, reduces mortality from bleeding.

Most deaths, in trauma and postpartum from hemorrhage, occur within hours of bleeding onset

The mortality benefit of TXA appears to diminish over time and is lost at 3 hours after major hemorrhage begins

In this trial, there was no evidence of adverse effects (vascular occlusive events) associated with TXA treatment

References:

Gayet-Ageron A et al. Effect of Treatment Delay on the Effectiveness and Safety of Antifibrinolytics in Acute Severe Haemorrhage: A Meta-Analysis of Individual Patient-Level Data From 40138 Bleeding Patients. Lancet 2017. PMID: 29126600

Hello Mike,
Great question, and the answer is yes. Not all providers or facilities are doing this, but it is my contention that this is the future of blood product resuscitation in trauma patients with major bleeding.